Uterine leiomyomas (fibroids) are the leading indication for hysterectomy in the United States. Despite the morbidity and high medical costs associated with fibroids, there has been little epidemiologic study of this condition in the United States. Uterine leiomyomas are histologically identifiable as benign smooth muscle tumors with varying amounts of associated fibrous tissue. Many women have more than one uterine leiomyoma, but each appears to be clonally distinct. Several specific cytogenetic changes have been identified in tumor tissue, but most show no chromosomal abnormalities. These benign tumors are hormone-dependent. They develop after puberty and regress after menopause. Both estrogen and progesterone are considered important stimulants, or at least permissive factors for tumor growth. To address the research needs in this field we have designed three studies. The first is a large epidemiologic study, the NIEHS Uterine Fibroid Study, designed to 1) estimate the age-specific cumulative incidence of leiomyomas in black and white women, aged 35-49, 2) identify risk factors for the condition, 3) compare growth mediating factors in tumor and matching myometrial tissues collected at time of hysterectomy, and 4) to identify factors associated with development of fibroid symptoms including pelvic pain and uterine bleeding. The second study (Barbara Davis, PI) is a clinical study of fibroids designed to describe fibroid growth and compare the growth-mediating factors in growing vs nongrowing tumors. The third study monitors fibroid change with pregnancy and postpartum uterine regression. We have followed the women in the original cumulative incidence study to monitor symptom development. The final field work will be completed in early 2005. After estimating the age-specific incidence of uterine fibroids for black and white women, we began to examine risk factors for uterine fibroids. Pregnancy is protective, though not those that occur before the mid twenties. Our hypothesis that viral infection increases risk was not supported by viral tissue markers. Alcohol appears to increase risk. In two cases we have replicated findings from animal models of fibroids. We find that the location of fibroids is somewhat different for parous and nonpauous women (9), and that prenatal exposure to DES is associated with increased development of fibroids. Increasing LH is associated with increased prevalence of the tumors, raising further doubts about the safety of hormone replacement therapy for women with fibroids. Using the data from ultrasound screening, we find that heavy uterine bleeding is greater for women with fibroids, especially large fibroids, but that submucous fibroids (those that abut the endometrium) are not more problematic than intramural (those within the muscle layer). Furthermore, women who know they have fibroids do not appear to over-report their symptoms. We have measured IGF-I and IGF-IBP3 in plasma samples from the study, and will examine these biological markers and fibroid occurrence. Summary histological measures of the tissue samples from the NIEHS Uterine Fibroid Study are continuing. We have enrolled approximately 100 women in the Postpartum Uterine Regression Study. The Fibroid Growth Study is continuing. Field work is scheduled to end September 30, 2004. Methods for measuring fibroid growth based on the MRI scans have been developed, and we are systematically assessing markers of proliferation, vascularity and collagen in the fixed tissues from surgical patients. Micro-array analyses have been completed and monthly questionnaire data have been used to develop pain and bleeding scales.